Case Study: Salbutamol/Salmeterol

Question 1

What is asthma?

Answer 1

Chronic inflammatory disorder of airways in response to external stimuli

Question 2

What are patients with asthma characterised by?

Answer 2

Inflammation
Bronchospasm

Question 3

What causes bronchodilation?

Answer 3

Adrenergic system

Question 4

What causes bronchoconstriction?

Answer 4

Cholinergic system

Question 5

What is used to treat bronchospasm?

Answer 5

Salbutamol
(Adrenergic agonist)
RELIEVER

Question 6

What is used to treat inflammation?

Answer 6

Corticosteroid
eg. beclomethasone

Question 7

Describe brief process of inflammation

Answer 7

Antigen + Ab (IgE)
A-A complex
Bronchoconstriction mediators
= histamine, leukotrienes + prostaglandins

Question 8

Describe 1st part of asthma drug history

Answer 8

Adrenaline
BUT cardiac effects
Agents similar to adrenaline structure
Isoprenaline = NO cardiac effects BUT short acting

Question 9

Describe 2nd part of asthma drug history

Answer 9

Adrenoreceptors
Alpha + beta

Question 10

What were alpha adrenoreceptors defined as?

Answer 10

Sensitive to adrenaline + insensitive to isoprenaline

Question 11

What were beta adrenoreceptors defined as?

Answer 11

Sensitive to isoprenaline + least sensitive to noradrenaline

Question 12

Describe the 3rd part of asthma drug history

Answer 12

Beta 1 receptors
Beta 2 receptors

Question 13

Where are beta 1 receptors found?

Answer 13

Heart

Question 14

Where are beta 2 receptors found?

Answer 14

Bronchial smooth muscle

Question 15

Describe the chemistry of noradrenaline + adrenaline

Answer 15

Very similar structure
Both acidic + basic groups
Physiologically behave as a base
= 90% protonated at pH 7.4

Question 16

Where is noradrenaline synthesised?

Answer 16

In neuron in CNS + autonomic nervous system

Question 17

Where is noradrenaline + adrenaline derived from?

Answer 17

L-tyrosine by series of enzyme catalysed reactions

Question 18

What is the aim of metabolism?

Answer 18

To change drugs so they have groups that make them more H2O soluble

Question 19

What type of receptors are adrenergic receptors?

Answer 19

G protein-coupled receptor

Question 20

How do adrenergic receptors affect biological activity?

Answer 20

Release secondary messenger molecules inside the cell after the bind an extracellular agonist

Question 21

How do noradrenaline bind?

Answer 21

Ionic bond
H bonds
Van der Waals

Question 22

What can noradrenaline interact with?

Answer 22

Alpha/ beta

Question 23

What can adrenaline interact with?

Answer 23

Alpha/ beta

Question 24

What does isoprenaline interact with?

Answer 24

Selectively beta

Question 25

What did the new drug need to be?

Answer 25

STABLE More selective for beta 2

Question 26

What did they first decide about the new formula?

Answer 26

Substituent had to be in meta position

Question 27

What was decided in round 2 of synthesis?

Answer 27

Tert-butyl derivative added = did increase some activity

Question 28

What was decided in round 3 of synthesis?

Answer 28

Methyl OH was added in meta position

Question 29

What did the tert-butyl group prevent?

Answer 29

CYP450 metabolism

Question 30

What was the only problem with salbutamol now? (New formulation)

Answer 30

Chiral compound = enantiomers one more active

Question 31

How do you separate enantiomers?

Answer 31

One will be insoluble to what the other will be soluble in

Question 32

Which enantiomer was more active of salbutamol?

Answer 32

R isomer

Question 33

What do substituents on amine groups determine?

Answer 33

Alpha or beta selectivity

Question 34

What do substituents on alpha C show?

Answer 34

An increased duration of action

Question 35

What needs to be substituted for an adrenergic agonist to demonstrate beta 2 selectivity?

Answer 35

Substituted ring: Phenolic hydroxy in para Substituent in meta for H bonding NEEDS to be resistant to COMT metabolism

Question 36

How long does salbutamol last?

Answer 36

4-6hrs BUT is a reliver

Question 37

What is salbutamol inadequate for?

Answer 37

Nocturnal bronchospasm

Question 38

For a long-acting beta 2 agonist what 2 major sites of interaction must it have?

Answer 38

Active site Hydrophobic domain for anchoring

Question 39

What were the 2 main observations from the LABA investigation?

Answer 39

To maintain potency 5-6 Cs To obtain long duration logP = 3.3 - 4.5

Question 40

What is the importance of O in LABA investigation?

Answer 40

O placed close to N O placed close to phenyl ring

Question 41

Describe the binding of Salmeterol

Answer 41

Reversible Can be repeated several times

Question 42

What problem was suggested about salmeterol?

Answer 42

Persists in tissues BUT interact freely + reversibly

Question 43

What was the original concept of salmeterol exo-site?

Answer 43

Long chain interacts with non-polar region in cell membrane “Exo-site” within vicinity of beta receptor